The anti-fibrotic effects of irisolidone via peroxisome proliferator-activated receptor gamma

Idiopathic pulmonary fibrosis is a progressive lung disorder with few effective therapies. Irisolidone, a natural flavonoid, exerts anti-inflammatory and antioxidant activities, but its inhibitory effects on pulmonary fibrosis have not been clarified. This study explored the protective effects and mechanism of irisolidone by regulating peroxisome proliferator-activated receptor gamma (PPARG) in TGF-β1-stimulated lung fibroblasts and bleomycin-induced mouse pulmonary fibrosis. Bioinformatics, molecular docking and thermal shift assays verified the potential modulation. In vitro, irisolidone mitigated fibroblast activation, inflammatory reactions and oxidative stress in a dose-dependent manner, which were abolished by PPARG knockdown. In vivo, irisolidone alleviated lung injury, collagen deposition and pathological fibrosis scores. GW9662 intervention partially offset its regulatory effects on the PI3K/Akt/mTOR pathway. No obvious short-term organ toxicity was found. Collectively, irisolidone regulating PPARG suppresses PI3K/Akt/mTOR signaling, reduces inflammation and oxidative stress and thereby exerts favorable anti-fibrotic effects in preclinical models. It shows potential as a candidate for anti-fibrotic study.